High-density lipoproteins (HDL) are blood-borne assemblies of protein and lipid that have been historically studied almost exclusively in the context of reverse cholesterol transport and the protection from cardiovascular disease. The purpose of this study is to explore a new link between HDL and the defense against invasive aspergillosis (IA), a life-threatening infection caused by the mold pathogen Aspergillus fumigatus. The most abundant protein found in HDL is apolipoprotein A-I (apoA-I), a lipid-binding molecule that underlies many of the cardioprotective functions attributed to these particles. Our preliminary data has shown that apoA-I(-/-) mice have dramatically increased susceptibility to experimental IA, demonstrating for the first time that lipoprotein metabolism and fungal pathogenesis are linked. AF-infected apoA-I(-/-) mice revealed a greater fungal burden, increased inflammation, and accelerated mortality compared to infected wild type mice. In vitro studies revealed that apoA-I binds to AF conidia and impairs germination, suggesting antifungal activity. In addition, the interaction of apoA-I with cultured macrophages enhanced their ability t kill conidia, suggesting that apoA-I has immunomodulatory effects that are relevant to fungal clearance. Based on these findings, we hypothesize that apoA-I protects against tissue injury during IA by (1) limiting fungal burden via inhibitory effects on the fungus and stimulatory effect on host cells, and (2) by adjusting the inflammatory response to promote clearance without triggering injurious hyperinflammation. Aim 1 will determine the mechanism by which apoA-I controls fungal burden during AF infection, focusing on direct antifungal effects as well as indirect effects on promoting the antifungal activity of innate immune cells. A major role for HDL in the circulation is preventing vascular inflammation; Aim 2 will determine the contribution of apoA-I to AF-induced inflammation and its relationship to fatal outcome in mouse models of IA. Finally, regardless of whether apoA-I protects against AF infection by controlling fungal burden (Aim 1) or by limiting destructive host inflammation (Aim 2), its beneficial effects suggest that manipulating apoA-I levels could be used to improve therapeutic outcome during IA. Aim 3 will test the hypothesis that pulmonary and/or systemic increases in apoA-I, or its peptide analogs, confer therapeutic protection against A. fumigatus. The findings from this study have the potential to bring treatments that are targeted to HDL, which are already in the developmental pipeline in the context of cardiovascular disease, into the realm of pulmonary protection in infectious disease. 1